PROTAC Degraders of SMARCA2 and SMARCA4 Proteins
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Solution Overview
Problem
Current small molecule ligands targeting SMARCA2 and SMARCA4 have failed to effectively inhibit cancerous cell proliferation due to their inability to phenocopy anti-proliferative effects, particularly in SMARCA4 mutated cancers, where SMARCA2 activity is crucial for maintaining oncogenic transcription.
Innovation Solution
Development of proteolysis targeting chimera (PROTAC) compounds that target the non-functional bromodomain of SMARCA2/4, conjugating a suitable SMARCA ligand with an E3 ligase binder to induce ubiquitylation and degradation of SMARCA proteins, thereby exploiting the vulnerability of SMARCA2 in SMARCA4 mutated cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule ligands target the bromodomain of SMARCA2/4, then binding to the target protein is achieved, but the ability to inhibit cancerous cell proliferation is insufficient
Solution Approach 1:
The patent introduces an E3 ligase as an intermediary component in the degradation pathway. The PROTAC molecule acts as a mediator that bridges the SMARCA2/4 target protein and the E3 ligase, forming a ternary complex that enables ubiquitylation and subsequent proteasomal degradation. This intermediary mechanism transforms the insufficient inhibition effect into effective anti-proliferative activity by completely eliminating the target protein rather than merely binding to it.
Solution Approach 2:
The patent changes the functional parameter of the target protein from 'bound state' to 'degraded state'. By designing PROTAC molecules that recruit E3 ligases, the system transitions the target protein from a bound complex (which showed insufficient inhibition) to ubiquitylated and proteasomally degraded forms, fundamentally altering the outcome parameter from partial inhibition to complete elimination of the oncogenic protein.
2Reliability
If PROTAC compounds are designed to degrade SMARCA2 and SMARCA4, then protein degradation is achieved, but the complexity of the molecular structure increases
Solution Approach 1:
The PROTAC molecule is segmented into three distinct functional modules: (1) a SMARCA2/4 ligand portion that binds the target protein, (2) a linker region that connects the two binding moieties, and (3) an E3 ligase binder portion that recruits the degradation machinery. This segmentation allows each component to perform its specific function while working together as an integrated system, achieving protein degradation despite the increased structural complexity.
Solution Approach 2:
The PROTAC represents a composite molecular structure combining elements from two different functional classes: a SMARCA2/4 bromodomain ligand and an E3 ligase inhibitor/binder. This composite design integrates the target recognition capability of the first component with the degradation-inducing capability of the second component, connected through a linker, thereby achieving protein degradation while managing the inherent complexity through modular composition.
3Quantity of substance
If classical small molecule drugs are used to inhibit SMARCA2/4 activity, then target binding is achieved, but selective degradation of the protein cannot be accomplished
Solution Approach 1:
Instead of using classical small molecule drugs that inhibit protein function through binding, the patent inverts the approach by designing molecules that promote protein degradation through ubiquitylation. The PROTAC does not simply bind and inhibit SMARCA2/4 activity; rather, it recruits E3 ligases to tag the target protein for destruction, fundamentally inverting the mechanism from functional inhibition to complete protein elimination, thereby achieving selective degradation that classical inhibitors cannot accomplish.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The PROTAC compounds effectively degrade SMARCA2 and SMARCA4 proteins, offering a therapeutic opportunity for treating cancers characterized by excessive cell proliferation, particularly those with SMARCA4 mutations, by selectively targeting and degrading these proteins, thus inhibiting cancerous cell growth.
Implementation Method 1
the close proximity of the ligase to the target results in target protein ubiquitylation
Implementation Method 2
The multi-ubiquitin chain on the target protein is then recognized by the proteasome and the target protein is degraded
Data Source
AI summary
The present invention encompasses compounds of formula (1)wherein the groups R1, A, G, LK and t have the meanings given in the claims and specification, their use as degraders of SMARCA2 and/or SMARCA4, pharmaceutical compositions which contain compounds of this kind and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.